CN103237446B - Clevidipine emulsion formulations containing antimicrobial agents - Google Patents

Clevidipine emulsion formulations containing antimicrobial agents Download PDF

Info

Publication number
CN103237446B
CN103237446B CN201180048865.XA CN201180048865A CN103237446B CN 103237446 B CN103237446 B CN 103237446B CN 201180048865 A CN201180048865 A CN 201180048865A CN 103237446 B CN103237446 B CN 103237446B
Authority
CN
China
Prior art keywords
exists
preparation
pharmaceutical
pharmaceutical preparation
clevidipine
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
CN201180048865.XA
Other languages
Chinese (zh)
Other versions
CN103237446A (en
Inventor
拉杰什瓦尔·马瑟拉姆
格雷戈里·查尔斯·威廉姆斯
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Chiesi Farmaceutici SpA
Original Assignee
Medicines Co
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Family has litigation
First worldwide family litigation filed litigation Critical https://patents.darts-ip.com/?family=45925617&utm_source=google_patent&utm_medium=platform_link&utm_campaign=public_patent_search&patent=CN103237446(B) "Global patent litigation dataset” by Darts-ip is licensed under a Creative Commons Attribution 4.0 International License.
Application filed by Medicines Co filed Critical Medicines Co
Publication of CN103237446A publication Critical patent/CN103237446A/en
Application granted granted Critical
Publication of CN103237446B publication Critical patent/CN103237446B/en
Ceased legal-status Critical Current
Anticipated expiration legal-status Critical

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4418—Non condensed pyridines; Hydrogenated derivatives thereof having a carbocyclic group directly attached to the heterocyclic ring, e.g. cyproheptadine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/205—Amine addition salts of organic acids; Inner quaternary ammonium salts, e.g. betaine, carnitine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/12—Carboxylic acids; Salts or anhydrides thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/16—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing nitrogen, e.g. nitro-, nitroso-, azo-compounds, nitriles, cyanates
    • A61K47/18—Amines; Amides; Ureas; Quaternary ammonium compounds; Amino acids; Oligopeptides having up to five amino acids
    • A61K47/183—Amino acids, e.g. glycine, EDTA or aspartame
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/22—Heterocyclic compounds, e.g. ascorbic acid, tocopherol or pyrrolidones
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/24—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing atoms other than carbon, hydrogen, oxygen, halogen, nitrogen or sulfur, e.g. cyclomethicone or phospholipids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/44—Oils, fats or waxes according to two or more groups of A61K47/02-A61K47/42; Natural or modified natural oils, fats or waxes, e.g. castor oil, polyethoxylated castor oil, montan wax, lignite, shellac, rosin, beeswax or lanolin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/10—Dispersions; Emulsions
    • A61K9/107—Emulsions ; Emulsion preconcentrates; Micelles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/12—Antihypertensives
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
    • Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
    • Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Medicinal Chemistry (AREA)
  • Epidemiology (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Oil, Petroleum & Natural Gas (AREA)
  • Engineering & Computer Science (AREA)
  • Dispersion Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Dermatology (AREA)
  • Molecular Biology (AREA)
  • Biophysics (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Diabetes (AREA)
  • Hematology (AREA)
  • Oncology (AREA)
  • Communicable Diseases (AREA)
  • Cardiology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicinal Preparation (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

Abstract

Pharmaceutical formulations comprising clevidipine and an antimicrobial agent exhibit a reduced propensity for microbial growth and provide increased convenience to health care workers administering clevidipine-containing formulations to patients.

Description

The clevidipine emulsion preparations that contains antimicrobial
Invention field
The present invention relates to a kind of stable, medicine oil in water emulsion preparation for parenteral, it comprises clevidipine (clevidipine) and antimicrobial.
Background of invention
Clevidipine is a kind of dihydropyridine calcium channel blocker, and it reduces by administration experimenter's blood pressure.It is characterized as being a kind of medicine of fugitive, high selectivity, and it shows half-life starting stage of approximately one minute and the t1/2 of about 15 minutes because its tachymetabolism is generally used for hospital environment.Can be at U.S. Patent number 5,856 about the more details of fugitive dihydropyridines, find in 346, the whole content of this patent is incorporated herein by reference as provided with its integral body.
The feature of clevidipine be also to have low-solubility in water and in lipid in paramount dissolubility.When clevidipine is dissolved in oil in water emulsion, it causes Billy with the better dissolubility of other conventional soln preparations and/or side effect still less. be a kind of clevidipine oil in water emulsion preparation, it for the treatment at acute hypertension, is mainly by U.S. FDA approval in emergency room and intensive care unit, and before operation, after operation neutralization operation the intravenous administration in environment.
can support growth of microorganism, because it contains soybean oil and egg yolk lecithin.Therefore, clevidipine oil in water emulsion preparation needs strict aseptic technique to avoid causing the microbial contamination of infection between patient during processing and administration.For the probability of minimise microbiological contamination, recommend such preparation to abandon for four hours after opening.Such requirement has applied burden to health-care hospital supplier, because must continue to obtain and prepare the fresh bottle of this medicine in treatment patient.Therefore, need to there is the stabilized chlorine Wei Taping emulsion preparations of larger antimicrobial properties, eliminate thus the risk of the microbial contamination in patient and the more convenience of processing is provided.Such preparation also will make health-care hospital supplier and patient save cost, and the waste and the minimizing that reduce clevidipine relate to the work consuming time of processing and replacing the bottle that holds this medicine.
Summary of the invention
Based on prior art, the object of this invention is to provide the stabilized chlorine Wei Taping emulsion preparations of the microbial contamination tendency with minimizing.
In the first embodiment of the present invention, a kind of pharmaceutical preparation is provided, it comprises clevidipine, or its medicinal salt or ester, antimicrobial, lipid, emulsifying agent, osmotic pressure regulator and water.
Aspect of this embodiment, the invention provides a kind of oil in water emulsion, wherein clevidipine is dispersed or dissolved in lipid, and in soybean oil, it is used egg yolk lecithin emulsifying in water again.The osmotic pressure of Emulsion regulates and is included in the EDTA that is enough to the amount of the growth of microorganism in inhibitory preparation in the situation of unexpected extraneous contamination with glycerol.
In the second aspect of this embodiment, the invention provides a kind of oil in water emulsion, wherein clevidipine is dispersed or dissolved in lipid, and in soybean oil, it is used egg yolk lecithin emulsifying in water again.The osmotic pressure of Emulsion regulates and is included in EDTA and the sodium citrate that is enough to the amount of the growth of microorganism in inhibitory preparation in the situation of unexpected extraneous contamination with glycerol.
In the second embodiment of the present invention, a kind of pharmaceutical preparation is provided, it comprises clevidipine, or its medicinal salt or ester, antimicrobial, lipid, emulsifying agent, coemulsifier, osmotic pressure regulator and water.
Aspect of this embodiment, the invention provides a kind of oil in water emulsion, wherein clevidipine is dispersed or dissolved in lipid, in soybean oil, it is used egg yolk lecithin emulsifying in water again, and wherein this Emulsion is also stabilized by coemulsifier oleic acid.The EDTA that the osmotic pressure of Emulsion regulates and comprises the amount that is enough to the growth of microorganism in inhibitory preparation with glycerol.
Second aspect in this embodiment, the invention provides a kind of oil in water emulsion, wherein clevidipine is dispersed or dissolved in lipid, in soybean oil, it is used egg yolk lecithin emulsifying in water again, and wherein this Emulsion is also stabilized by coemulsifier oleic acid.The osmotic pressure of Emulsion regulates and is included in EDTA and the sodium citrate that is enough to the amount of the growth of microorganism in inhibitory preparation in the situation of unexpected extraneous contamination with glycerol.
In the 3rd embodiment of the present invention, a kind of pharmaceutical preparation is provided, it comprises clevidipine, or its medicinal salt or ester, antimicrobial, antioxidant, lipid, emulsifying agent, osmotic pressure regulator and water.
Aspect of this embodiment, the invention provides a kind of oil in water emulsion, wherein clevidipine is dispersed or dissolved in lipid, and in soybean oil, it is again by also stabilized by antioxidants ascorbic acid sodium with egg yolk lecithin emulsifying in water.The EDTA that the osmotic pressure of Emulsion regulates and comprises the amount that is enough to the growth of microorganism in inhibitory preparation with glycerol.
In the 4th embodiment of the present invention, a kind of pharmaceutical preparation is provided, it comprises clevidipine, or its medicinal salt or ester, antimicrobial, antioxidant, lipid, emulsifying agent, coemulsifier, osmotic pressure regulator and water.
Aspect of this embodiment, the invention provides a kind of oil in water emulsion, wherein clevidipine is dispersed or dissolved in lipid, in soybean oil, it is again by with egg yolk lecithin emulsifying in water, and wherein this Emulsion also by coemulsifier oleic acid by stabilisation physically and by antioxidants ascorbic acid sodium by stabilisation chemically.The EDTA that the osmotic pressure of Emulsion regulates and comprises the amount that is enough to the growth of microorganism in inhibitory preparation with glycerol.
In the aspect of the embodiment that described preparation comprises antioxidant therein, antioxidant can reduce the formation of oxidative breakdown product H324/78 and H152/66.
In aspect each embodiment of the present invention preferred, described antimicrobial is alcohol or chelating agen.More preferably, described antimicrobial is ethylenediaminetetraacetic acid (EDTA) disodium or sodium citrate, or these two.
In aspect each embodiment of the present invention preferred, described pharmaceutical preparation is aseptic.The in the situation that of accidental pollution, described pharmaceutical preparation at least about 24 hours by obstruction microbial growth to being no more than 1log.
In each embodiment of the present invention, clevidipine and Emulsion keep their stability in preparation.In each embodiment of the present invention, described pharmaceutical preparation is for parenteral.In each embodiment of the present invention, the scope of the pH that described pharmaceutical preparation has is approximately 6.0 to approximately 8.8.
Accompanying drawing summary
The detailed description to embodiment of the present invention by considering to carry out below in conjunction with accompanying drawing, will be conducive to understand the present invention:
Fig. 1: clevidipine degradation pathway.
Detailed Description Of The Invention
Should be appreciated that accompanying drawing of the present invention has been simplified to illustrate the key element relevant to clearly understanding the present invention with describing, and has removed many other key elements that exist in typical pharmaceutical compositions and stabilization method simultaneously for purposes of clarity.Those skilled in the art will recognize that, other key elements and/or step in realizing the present invention, be expectation and/or need.Yet, because such key element and step are known in this area, and because they are not conducive to understand better the present invention, so do not provide in this article such medicine and the discussion of step.Disclosure herein relates to all such change and modifications to such key element well known by persons skilled in the art and method.In addition, determine herein and illustrational embodiment only for exemplary purpose, and do not mean that and be exclusive or be limited to description of them in the present invention.
As used herein, term " clevidipine " should represent and comprise all kinds or the form of clevidipine.Unless otherwise prescribed, the example of such form comprises all pharmaceutical salts, ester, isomer, stereoisomer, crystallization and amorphous form.An instantiation is butyrate clevidipine.In preparation of the present invention, the amount of clevidipine can change according to the concentration of total overall volume of preparation and other components.Yet the scope of the amount of the clevidipine in described preparation is generally approximately 0.005 to about 1.0%w/v, and comprise approximately 0.03 scope to about 0.5%w/v, and approximately 0.01 to about 1.0%w/v.In specific embodiments, the amount of the clevidipine in preparation is approximately 0.05,0.1 or 0.3%w/v.
As used herein, term " pharmaceutical salts " should refer to that preparation is from comprising the medicinal nontoxic alkali of inorganic or organic base and inorganic or organic acid or the salt of acid.Example derived from the salt of inorganic base comprises aluminum, ammonium, calcium, copper, ferrum, ferrous iron, lithium, magnesium, manganese salt, sub-manganese, potassium, sodium, zinc etc.Particularly preferably be ammonium, calcium, magnesium, potassium and sodium salt.Salt derived from medicinal organic nontoxic alkali comprises following salt: primary amine, secondary amine and tertiary amine, the replacement amine that comprises natural replacement amine, cyclammonium and deacidite, as arginine, betanin, caffeine, gallbladder alkali, N, N '-dibenzyl-ethylenediamin, diethylamine, 2-diethylaminoethanol, DMAE, ethanolamine, ethylenediamine, N-ethyl-morpholine, N-ethylpiperidine, glycosamine, aminoglucose, histidine, breathe out amine (hydrabamine), 2-aminopropane., lysine, methylglucosamine, morpholine, piperazine, piperidines, polyamino resin, procaine, purine, theobromine, triethylamine, trimethylamine, tripropyl amine (TPA), butantriol ammonia etc.
As used herein, term " medicinal ester " should refer to the ester of preparing with reacting of hydroxy-containing compounds by oxyacid.Conventionally, ester is derived from inorganic or organic acid and alcohol.More generally, ester is prepared by condensation organic acid and alcohol.Can comprise butyrate for the example of the suitable esters of preparation of the present invention, as those esters of preparing according to the instruction in U.S. Patent number 5856346,5739152,6350877 etc.
Clevidipine, by 4-(2 ', 3 '-Dichlorobenzene base)-Isosorbide-5-Nitrae-dihydro-5-methoxycarbonyl group-2, is prepared acquisition clevidipine thereby 6-dimethyl-acidum nicotinicum react with butanoic acid chloromethyl ester.This reaction can be optionally at corresponding bicarbonate as KHCO 3under existence, in backflow acetonitrile, carry out.Inorganic salt can by remove by filter and product by adding isopropyl alcohol and water crystallisation by cooling subsequently.Can also by by solvent from acetonitrile replace with alcohol as the mixture of ethanol or isopropyl alcohol and water, utilize repeated evaporation to make its crystallization.In being further purified of product, the washing of the mixture of crystal water and ethanol or isopropyl alcohol.Product can be dissolved in backflow isopropyl alcohol, by crystallisation by cooling, by isolated by filtration and last water and isopropanol mixture, washs.The more detailed description of the manufacture method of clevidipine can be at U.S. Patent number 6,350, finds in 877, and the whole disclosure of described patent is incorporated herein by reference as provided with its integral body.As used in this article, in preparation, the scope of operable clevidipine comprises approximately 0.005% scope to about 1%w/v.
Contain clevidipine responsive to water, light and heat as the compositions of active component.Clevidipine is degraded to the plurality of impurities of infringement clevidipine effect under unfavorable conditions.The degradative pathway of clevidipine is shown in Fig. 1.A large amount of clevidipine catabolites have been differentiated in this path, comprise for example H152/81, H168/79, H207/59, H324/78 and H152/66.
About any exemplary of pharmaceutical composition as herein described, preferably, in described compositions, the level of clevidipine impurity is low as far as possible.Therefore, although the various exemplary of pharmaceutical composition be included in for compositions as a whole, can accept and effective range in impurity level, compositions is purer, described compositions is expectation more.Be present in the amount of the clevidipine catabolite in preparation of the present invention lower than approximately 5%, 3%, 2%, 1%, 0.9%, 0.8%, 0.7%, 0.6%, 0.5%, 0.4%, 0.3% or 0.2%, or even still less.
Pharmaceutical preparation of the present invention is emulsion preparations.For the compound in water with poor dissolubility and stability, Emulsion provides than the better dissolubility of conventional aqueous solution and stability.Oil in water emulsion also prevents that described compound from adhering to the plastic infusion device using when this compound of administration.Can be at U.S. Patent number 5,739 about the further information of clevidipine preparation, find in 152, the whole disclosure of described patent is incorporated herein by reference as provided with its integral body.
As used herein, term " antimicrobial " represents to suppress microorganism as the reagent of antibacterial and fungus (Molds and yeasts) growth.The concrete kind of antimicrobial comprises chelating agen and alcohol.Chelating agen includes but not limited to ethylenediaminetetraacetic acid (EDTA) and salt, citric acid and salt thereof etc.Exemplary chelating agen is disodiumedetate and sodium citrate.Alcohol includes but not limited to benzylalcohol and methaform.Representative antimicrobial comprises EDTA, ascorbic acid, BHA/BHT, benzylalcohol, benzoic acid, citric acid, ethylenediaminetetraacetic acid, parabens, phenol, propyl gallate, sorbic acid, sodium sulfite, sodium sulfite, benzoic acid, methaform, chlorocresol, cresol, dehydroactic acid, phenol, Potassium Benzoate, potassium sorbate, sodium benzoate, dehydro sodium acetate, sodium propionate, sorbic acid, thymol, benzalkonium chloride, benzethonium chloride, butyl p-hydroxybenzoate, cetylpyridinium chloride, ethylparaben, methyl parahydroxybenzoate, Sodium Methyl Hydroxybenzoate, propyl p-hydroxybenzoate, Sodium Propyl Hydroxybenzoate, chlorocresol, cresol, dehydroactic acid, ethylparaben, methyl parahydroxybenzoate, Sodium Methyl Hydroxybenzoate, phenol, potassium sorbate, thimersol and from the various salt forms of these compounds.
Conventionally, term " EDTA " represents ethylenediaminetetraacetic acid and its derivant and its salt.The concrete derivant of using in the present invention comprises disodiumedetate.The character of EDTA derivant or salt is not critical, as long as it suppresses the growth of microorganism in preparation of the present invention.
The amount of the antimicrobial in preparation of the present invention can change according to the concentration of total overall volume of preparation and other components.Yet the common scope of amount of the antimicrobial in described preparation is approximately 0.001 to about 1.5%w/v, and comprises that approximately 0.005 to about 0.5%w/v, approximately 0.001 to about 0.1%w/v, and approximately 0.01 to about 0.1%w/v, and approximately 0.1 to about 1%w/v.In specific embodiments, the amount of the antimicrobial in preparation is approximately 0.1,0.2 or 0.4%w/v.In the situation that using chelating agen as antimicrobial, the scope of the amount of the chelating agen in preparation is generally approximately 0.001% to about 0.5%w/v.Antimicrobial can comprise one or more reagent, as the different antimicrobials such as two kinds, three kinds, four kinds.
As used herein, " antioxidant " in term preparation comprises sodium ascorbate, cysteine hydrochloride, sodium sulfite, sodium pyrosulfite, sodium sulfite, ascorbyl palmitate, Butylated hydroxyanisole (BHA), Yoshinox BHT (BHT), propyl gallate, tocopherol, and their pharmaceutical salts.Exemplary antioxidant is sodium ascorbate.The amount of the antioxidant in preparation of the present invention can change according to the concentration of total overall volume of preparation and other components.Yet the scope of the amount of the antioxidant in preparation is generally approximately 0.01 to about 1.0%w/v, and comprise that approximately 0.05 to about 1.0%w/v, and approximately 0.05 to about 0.5%w/v.In specific embodiments, the amount of the antioxidant in preparation is about 0.1%w/v.
As used herein, " lipid " in term preparation is any medicinal oil, and preferably glycerine three esters are if soybean oil, safflower oil, olive oil, Oleum Gossypii semen, sunflower oil, Oleum sesami, Oleum Arachidis hypogaeae semen, Semen Maydis oil, medium chain triglyceride are (as Miglyol tM812 or 810) or glyceryl triacetate.Described lipid can be also polyethylene glycol di or monoglyceride (as acetylareal monoglyceride).Described lipid can also be one or more the mixture in these lipids.A kind of exemplary lipid is soybean oil.The amount of the lipid in preparation of the present invention can change according to the concentration of total overall volume of preparation and other components.Yet the scope of the amount of the lipid in preparation is generally approximately 2 to about 30%w/v, and comprise that approximately 5 to about 30%w/v, and approximately 10% to about 20%w/v.In specific embodiments, the amount of the lipid in preparation is about 20%w/v.
As used herein, term " emulsifying agent " represents the suitable medicinal surfactant using in preparation, the natural phospholipid preferably extracting from egg yolk or Semen sojae atricolor, synthetic phosphatidylcholine or from the phosphatidylcholine of the purification of plant origin.Also can use hydrogenated derivatives, as the phosphatldylcholine (Semen sojae atricolor) of the phosphatldylcholine of hydrogenation (egg) and hydrogenation.The amount of the phospholipid emulsifier in preparation of the present invention can change according to the concentration of total overall volume of preparation and other components.Yet the scope of the amount of the emulsifying agent in preparation is generally approximately 0.2 to about 2.0%w/v, and comprise that approximately 0.5 to about 1.5%w/v.In specific embodiments, the amount of the emulsifying agent in preparation is about 1.2%w/v.
As used herein, term " coemulsifier " represents to be included in the second medicinal surfactant in preparation of the present invention.Such surfactant comprises that synthetic non-ionic surface active agent for example, as poloxamer (poloxamer) (PLURONICS F87 and 407), Cremophor (cremophor) tMthe husky amine (poloxamine) in pool Lip river, Myrj 45, polyoxyethylene sorbitan fatty acid ester or fatty acid esters of sorbitan, the derivant of tocopherol is as tocopherol PEG succinate, and long-chain fatty acid is as oleic acid, stearic acid, Palmic acid, bile acid is as cholic acid and deoxycholic acid or surface activity derivant, and pharmaceutical salts.A kind of exemplary surfactant is oleic acid.When existing, the amount of the coemulsifier in preparation of the present invention can change according to the concentration of total overall volume of preparation and other components.Yet the scope of the amount of the surfactant in preparation is generally approximately 0.005 to about 2%w/v, and comprise that approximately 0.01 to about 2%w/v, and approximately 0.01 to about 1.0%w/v.In specific embodiments, the amount of the surfactant in preparation is about 0.03%w/v.
As used herein, " osmotic pressure regulator " in term preparation of the present invention comprises sodium chloride, potassium chloride, mannitol, sucrose, lactose, fructose, maltose, glucose, anhydroglucose, propylene glycol, glycerol and glycerol.A kind of exemplary osmotic pressure regulator is glycerol.The amount of the osmotic pressure regulator in preparation of the present invention can change according to the concentration of total overall volume of preparation and other components.Yet the scope of the amount of the osmotic pressure regulator in preparation is generally approximately 2 to about 3%w/v, and comprise that approximately 2 to about 2.75%w/v.In specific embodiments, the amount of the osmotic pressure regulator in preparation is about 2.25%w/v.Term " osmotic pressure regulator " and " isotonicity regulator " are used interchangeably in this article.
Water in preparation of the present invention is used for volume be supplemented to 100%w/v and can change according to the concentration of total overall volume of preparation and other components as the amount of water for injection.
When described preparation is designed for parenteral, it will be appreciated by those skilled in the art that one or more other components that can comprise for parenteral administration.Other component like this comprises that stabilizing agent is (for example sugared, aminoacid and polysorbate, as 5% glucose), solubilizing agent (cetrimonium bromide (cetrimide) for example, docusate sodium (sodium docusate), glyceryl monooleate, polyvinylpyrrolidone (PVP) and Polyethylene Glycol (PEG), buffer agent (acetate for example, citrate, phosphate, tartrate, lactate, succinate, aminoacid etc.), antiseptic (BHA for example, BHT, gentisic acid, vitamin E, ascorbic acid, sodium ascorbate and sulfur-bearing regent are as sulphite, bisulfites, metabisulfite, sulfo-glycerol, thioglycolate salt etc.), suspending agent or sticky agent, chelating agen, and administration auxiliary agent (local anesthetic for example, antiinflammatory, anticoagulant, for vasoconstrictor and the infiltrative reagent of augmenting tissue extending).
Parenteral mode of administration includes but not limited in Intradermal, subcutaneous (s.c., s.q., sub-Q, Hypo), intramuscular (i.m.), intravenous (i.v.), intraperitoneal (i.p.), intra-arterial, marrow, in heart heart, in intraarticular (joint), synovial membrane in (liquid zone, joint), intracranial, spinal column and in sheath (spinal fluid).Can be with can be used for the parenteral injection of pharmaceutical preparation or any known devices of perfusion realizes such administration.
In intravenous is used, sterile preparation of the present invention can be dissolved or suspended in any conventional aseptic intravenous fluid and by perfusion administration.Intravenous fluid includes but not limited to normal saline, phosphate buffered saline (PBS), 5% glucose in water or Ringer ' s tMsolution.The parenteral dosage forms of preparation of the present invention can be for example also ready-to-use (ready-to-use) solution in the ampoule of sterile sealing bottle, airtight sealing or aseptic prefilled syringe (pre-filled syringe).
Aseptic prefilled syringe is the syringe that accommodates the pharmaceutical preparation of the present invention of unit dose.Suitable syringe can extensively obtain and know for those skilled in the art.A kind of exemplary aseptic prefilled syringe is to have loaded the pharmaceutical preparation of unit dose and be encapsulated in opaque, the syringe in packing of having got rid of oxygen.For example, oxygen can be used CO 2and/or N 2displacement.
The scope of the pH of pharmaceutical preparation of the present invention is approximately 6.0 to approximately 8.8.In specific embodiments, pH scope is approximately 6.5 to approximately 8.0.In specific embodiments, pH is 6.2,6.5,6.75,7.0 or 7.5.Can use alkali as NaOH, KOH and Ca (OH) 2realize the pH of expectation.
As used in this article, term " inhibition ", " prevention " and " restriction " have their common and conventional sense, and comprise anti-bacteria or the growth of fungus in preparation of the present invention.Such inhibition was no more than the growth of approximately 10 times after can being described as be in the extraneous contamination of low-level (1-1000Cfu/mL) at least 24 hours.Such growth can be for example by determining that the quantity of colony-forming units is determined when the incubated at room temperature.
Keep to suppress the environmental condition that persistent period of growth of microorganism exposes according to preparation, for example, by the sterile vials of needle-penetration preparation or the condition of otherwise destroying aseptic, change.Yet in one embodiment of the invention, after described preparation is exposed to low-level external microbial contamination, growth of microorganism is suppressed reaches at least about more than 24 hours.
Technical staff will understand, and the device for the preparation of emulsion preparations that pharmaceutical preparation of the present invention can be used this area to accept is prepared.General procedure for the preparation of chlorine Wei Taping preparation is described below: the oil phase that contains soybean oil, clevidipine and egg yolk lecithin is mixed to form thick Emulsion with the water that contains glycerol at about 70 ℃.Use sodium hydroxide to regulate the pH of this thick Emulsion.After pH regulator, under high pressure this thick Emulsion is homogenized to produce fine granularity and therefore produce stable Emulsion.Pack this Emulsion in appropriate containers and in autoclave sterilizing.
With reference to following non-limiting example, the present invention is described in more detail.
Embodiment 1-5
Embodiment 1-is by joining the liquid storage of antimicrobial to be prepared as follows the preparation that contains antimicrobial shown in table 1 in chlorine Wei Taping Emulsion with debita spissitudo.
Table 1
Growth of microorganism to the aseptic clevidipine oil-in-water compositions of preparing is as mentioned above evaluated.With standard UPS test organisms, carry out test microbes growth inhibited.Each preparation is tested for five kinds of standard USP test organismss: staphylococcus aureus (S.aureus) (SA, ATCC#6538), Pseudomonas aeruginosa (P.aeruginosa) (PA, ATCC#9027), escherichia coli (E.coli) (EC, ATCC#8739), Candida albicans (C.albicans) (CA, ATCC#10231) and aspergillus niger (A.niger) (AN, ATCC#16404).With the suspension of every kind of bacterium, with each filter, reclaiming the amount that is less than 100CFU (colony-forming units) inoculates to preparation.The inoculation of every kind of preparation is carried out in triplicate.
During studying, test specimen is stored in to 20-25 ℃.At postvaccinal 0,24 and 48 hour, constantly test.At reasonable time point, sample filtered by 0.45 micron membranes filter and use 0.1% sterile peptone solution to wash to remove antiseptic, thereby reclaiming microorganism.Filter after washing sterilely takes out and is placed on suitable microbiological culture media.
Staphylococcus aureus, Pseudomonas aeruginosa and escherichia coli are laid on tripticase soy agar and 30-35 ℃ of aerobic incubation 2 days or until form isarithmic bacterium colony, whichsoever first generation.Candida albicans and aspergillus niger are laid on Saab sieve (sabouraud) agar glucose and 20-25 ℃ of aerobic incubation 7 days or until form isarithmic bacterium colony, whichsoever first generation.
If exist the increase that outbreak postpones or growth is slowed down so that viable bacteria falls within the time of 24 hours to be less than 10 times (1log), think that Antimicrobial is acceptable.
In 24 hours, EDTA (individually or in conjunction with benzylalcohol) is presented in following table 2 effect of Antimicrobial.From these experiments, can infer that the existing of EDTA and benzylalcohol (individually or in combination) shows microorganism retardance ability.
Table 2
TNTC=can not count too much
C=confluent growth
Embodiment 2-is by joining the liquid storage of antimicrobial to be prepared as follows the preparation that contains antimicrobial shown in table 3 in chlorine Wei Taping Emulsion with suitable concentration.
Table 3
According to the program of describing before, the growth of microorganism of assessment above-mentioned composition.The effect of EDTA combining citric acid sodium or the sodium ascorbate delay growth of microorganism in 24 hours is presented in following table 4.From these experiments, can infer that the existence of EDTA combining citric acid sodium or sodium ascorbate shows microorganism retardance ability.
Table 4
TNTC=can not count too much
C=confluent growth
Embodiment 3-is exposed to high-strength light (combination of cold white fluorescent and black light) by clevidipine emulsion preparations, to confirm light to the impact of chemical stability and to the results are shown in following table 5:
Table 5
Find unexpectedly, under EDTA exists, add the light degradation that ascorbic acid suppresses the chlorine Wei Taping in Emulsion effectively, and do not offset the antimicrobial efficacy of EDTA.
Embodiment 4-is as a part for emulsion process, the clevidipine emulsion preparations by adding EDTA and/or sodium citrate preparation with EDTA (be combined individually or with sodium citrate), the antimicrobial property of observing before in the Emulsion that is added to preparation as solution time for confirmation.Emulsion preparations shown below is prepared as follows: the oil phase that contains soybean oil and egg yolk lecithin is mixed to form thick Emulsion with the water that contains glycerol, disodiumedetate (being with or without sodium citrate) and water at about 70 ℃.Use sodium hydroxide to regulate the pH of this thick Emulsion.After pH regulator, under high pressure this thick Emulsion is homogenized to produce fine granularity and therefore produce stable Emulsion.This Emulsion is packed in suitable container and sterilizing in autoclave.
Evaluation and the result of these preparations being carried out to growth of microorganism inhibition are presented in following table 6.
Table 6
Result shows, the EDTA of variable concentrations (individually or combining citric acid sodium) effective retardance growth of microorganism when the part as preparation method is added.
Embodiment 5-has the physical stability of the Emulsion of antimicrobial and evaluates via zeta potential measurement.Determine the zeta potential of measuring as oil droplet electric charge around, to evaluate the physical stability of the emulsion preparations that contains antimicrobial.The zeta potential of larger absolute value causes the Coulomb repulsion increasing between oil droplet and indicates the physical stability strengthening.Result confirms, the absolute value of zeta potential (individually or combining citric acid sodium) under EDTA exists reduces, and this is surprising under the low condition of known their concentration.
In order to improve the physical stability of Emulsion, studied the use of oleic acid (coemulsifier).The clevidipine Emulsion with oleic acid as shown in following examples is used following technique preparation: the oil phase that contains soybean oil, clevidipine, egg yolk lecithin and oleic acid is mixed to form thick Emulsion with the water that contains glycerol, disodiumedetate and water at about 70 ℃.Use sodium hydroxide to regulate the pH of this thick Emulsion.After pH regulator, under high pressure this thick Emulsion is homogenized to produce fine granularity and therefore produce stable Emulsion.Pack this Emulsion into appropriate containers and sterilizing in autoclave.
Table 7
Zeta potential and the growth of microorganism of evaluating above-mentioned composition suppress.
The growth of microorganism that reaches the embodiment 12 of 12,24 and 30 hours suppresses to be presented in following table 8.
Table 8
The result of zeta potential is presented in following table 9 and confirms, than the Emulsion that comprises EDTA independent or that be combined with sodium citrate, the oleic acid that comprises low concentration shows the zeta potential of Emulsion and the remarkable increase of physical stability unexpectedly.
Table 9
In addition, as shown in following table 10, oleic acid does not affect the antimicrobial efficacy of EDTA.
Table 10

Claims (20)

1. a pharmaceutical preparation, described pharmaceutical preparation comprises:
(a) clevidipine, or its medicinal salt or ester, it exists with 0.01 to 1.0%w/v,
(b) antimicrobial, it exists with 0.001 to 1.0%w/v,
(c) lipid, it exists with 2 to 30%w/v,
(d) emulsifying agent, it exists with 0.2 to 2.0%w/v,
(e) osmotic pressure regulator, it exists with 2 to 3%w/v, and
(f) water, to 100%.
2. pharmaceutical preparation according to claim 1, wherein said preparation further comprises antioxidant, it exists with 0.01 to 1.0%w/v.
3. pharmaceutical preparation according to claim 2, wherein said preparation further comprises coemulsifier, it exists with 0.01 to 2%w/v.
4. according to the pharmaceutical preparation described in claim 1-3 any one, wherein said antimicrobial choosing is the group of following composition freely: benzylalcohol, EDTA, sodium ascorbate, citric acid, and their mixture, derivant and salt.
5. according to the pharmaceutical preparation described in claim 1-3 any one, the choosing of wherein said lipid is the group of following composition freely: soybean oil, safflower oil, olive oil, Oleum Gossypii semen, Oleum Helianthi, Oleum sesami, Oleum Arachidis hypogaeae semen, Semen Maydis oil, medium chain triglyceride, glyceryl triacetate, propylene glycol diesters, monoglyceride, and two or more the mixture in them.
6. according to the pharmaceutical preparation described in claim 1-3 any one, the choosing of wherein said emulsifying agent is the group of following composition freely: egg yolk lecithin, soybean phospholipid, synthetic phosphatidylcholine, purification phosphatidylcholine and HSPC, and two or more the mixture in them.
7. according to the pharmaceutical preparation described in claim 1-3 any one, wherein said preparation is contained in aseptic prefilled syringe.
8. according to the pharmaceutical preparation described in claim 2 or 3, wherein said antioxidant choosing is the group of following composition freely: sodium ascorbate, sodium citrate, cysteine hydrochloride, sodium bisulfate, sodium pyrosulfite, sodium sulfite, ascorbyl palmitate, Butylated hydroxyanisole, Yoshinox BHT, propyl gallate, tocopherol, and pharmaceutical salts.
9. pharmaceutical preparation according to claim 3, wherein said coemulsifier choosing is the group of following composition freely: glycerol, glycerol, poloxamer, Cremophor tM, the husky amine in pool Lip river, Myrj 45, polyoxyethylene sorbitan fatty acid ester, fatty acid esters of sorbitan, polysorbate, tocopherol PEG succinate, cholic acid, deoxycholic acid, oleic acid, and pharmaceutical salts.
10. pharmaceutical preparation according to claim 3, wherein in described preparation H324/78 with 0.2% or exist below.
11. 1 kinds of pharmaceutical preparatioies, described pharmaceutical preparation comprises:
(a) butyrate clevidipine, it exists with 0.01 to 1%w/v,
(b) EDTA, it exists with 0.001 to 0.1%w/v,
(c) soybean oil, it exists with 4 to 30%w/v,
(d) egg yolk lecithin of purification, it exists with 0.2 to 2%w/v,
(e) glycerol, it exists with 2 to 3%w/v, and
(f) water, to 100%.
12. pharmaceutical preparatioies according to claim 11, wherein said pharmaceutical preparation further comprises sodium citrate, and it exists with 0.005 to 0.5%w/v.
13. pharmaceutical preparatioies according to claim 11, wherein said pharmaceutical preparation further comprises sodium ascorbate, and it exists with 0.01 to 1%w/v.
14. pharmaceutical preparatioies according to claim 11, wherein said pharmaceutical preparation further comprises oleic acid, and it exists with 0.01 to 2.0%w/v.
15. pharmaceutical preparatioies according to claim 14, wherein said pharmaceutical preparation further comprises sodium citrate, and it exists with 0.005 to 0.5%w/v.
16. pharmaceutical preparatioies according to claim 14, described pharmaceutical preparation further comprises sodium ascorbate, and it exists with 0.05 to 1.0%w/v.
17. according to the pharmaceutical preparation described in claim 1 or 11, and the pH of wherein said preparation is 6.0 to 8.8.
18. pharmaceutical preparatioies according to claim 1, wherein said antimicrobial is chelating agen.
19. pharmaceutical preparatioies according to claim 1, wherein said antimicrobial is EDTA, it exists with 0.001 to 0.025%w/v.
20. pharmaceutical preparatioies according to claim 19, wherein said antimicrobial is EDTA, it exists with 0.001 to 0.01%w/v.
CN201180048865.XA 2010-10-12 2011-10-10 Clevidipine emulsion formulations containing antimicrobial agents Ceased CN103237446B (en)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
US39229410P 2010-10-12 2010-10-12
US61/392,294 2010-10-12
PCT/US2011/055617 WO2012051116A1 (en) 2010-10-12 2011-10-10 Clevidipine emulsion formulations containing antimicrobial agents

Publications (2)

Publication Number Publication Date
CN103237446A CN103237446A (en) 2013-08-07
CN103237446B true CN103237446B (en) 2014-11-05

Family

ID=45925617

Family Applications (1)

Application Number Title Priority Date Filing Date
CN201180048865.XA Ceased CN103237446B (en) 2010-10-12 2011-10-10 Clevidipine emulsion formulations containing antimicrobial agents

Country Status (18)

Country Link
US (1) US10010537B2 (en)
EP (1) EP2627173B2 (en)
JP (3) JP6040437B2 (en)
KR (2) KR20130101080A (en)
CN (1) CN103237446B (en)
AU (1) AU2011313852B2 (en)
BR (1) BR112013008601B1 (en)
CA (1) CA2814495C (en)
DK (1) DK2627173T4 (en)
EA (1) EA022849B1 (en)
ES (1) ES2539861T5 (en)
HK (1) HK1187495A1 (en)
HU (1) HUE026295T2 (en)
MX (2) MX2013004151A (en)
NZ (1) NZ610465A (en)
PL (1) PL2627173T5 (en)
PT (1) PT2627173E (en)
WO (1) WO2012051116A1 (en)

Families Citing this family (18)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
PL2320740T3 (en) 2008-08-01 2014-09-30 The Medicines Co Pharmaceutical compositions of clevidipine and methods for producing low impurity concentrations of the same
US8658676B2 (en) 2010-10-12 2014-02-25 The Medicines Company Clevidipine emulsion formulations containing antimicrobial agents
PT2627173E (en) 2010-10-12 2015-07-24 Medicines Co Clevidipine emulsion formulations containing antimicrobial agents
CN103781479A (en) * 2011-04-01 2014-05-07 医药公司 Short-acting dihydropyridines (clevidipine) for use in reducing stroke damage
CA2889584C (en) * 2012-10-26 2018-08-14 The Medicines Company Methods for controlling blood pressure and reducing dyspnea in heart failure
CN103169672A (en) * 2012-12-26 2013-06-26 辰欣药业股份有限公司 Clevidipine butyrate freeze-dried emulsion
CN103110580B (en) * 2013-02-20 2014-09-17 北京德立福瑞医药科技有限公司 Clevidipine butyrate injection
CN103126986A (en) * 2013-03-19 2013-06-05 董慧芳 Emulsion for clevidipine butyrate intravenous injection and preparation method thereof
TW201538181A (en) * 2014-03-19 2015-10-16 Pures Biotech Co Ltd A semi-fluid composition for lubricating, moisture retaining, disinfecting and sterilizing
CA2947486C (en) * 2014-05-19 2023-09-26 The Medicines Company Clevidipine nanoparticles and pharmaceutical compositions thereof
CN105456189A (en) * 2014-09-12 2016-04-06 武汉大安制药有限公司 Clevidipine butyrate emulsion injection and preparation method thereof
CN104523590B (en) * 2014-12-09 2017-09-15 山东威高药业股份有限公司 A kind of Clevidipine butyrate fat emulsion injection
CN107661294B (en) * 2016-07-27 2020-04-14 武汉科福新药有限责任公司 Anti-hypertension drug fat emulsion injection and preparation method thereof
WO2019123221A1 (en) * 2017-12-20 2019-06-27 Aurobindo Pharma Limited Pharmaceutical composition comprising clevidipine and process for preparation thereof
CN108324703B (en) * 2018-01-26 2020-07-28 中国医学科学院阜外医院 Injection for protecting ischemic myocardium and preparation method thereof
CN109602704A (en) * 2019-01-23 2019-04-12 广东嘉博制药有限公司 Clevidipine butyrate fat emulsion injection and its preparation process
CN109776405A (en) * 2019-03-07 2019-05-21 重庆安格龙翔医药科技有限公司 A kind of preparation method of butyrate clevidipine impurity
US11135208B2 (en) 2019-08-12 2021-10-05 American Regent, Inc. 1,4-dihydropyridine compositions, methods of making and use

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2010022259A1 (en) * 2008-08-22 2010-02-25 Milestone Pharmaceuticals Inc. Short acting benzothiazepine calcium channel blockers and uses thereof
US20100105743A1 (en) * 2008-08-01 2010-04-29 Gopal Krishna Pharmaceutical compositions and methods for stabilizing the same

Family Cites Families (34)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE4217842A1 (en) 1992-05-29 1993-12-02 Dietl Hans Pharmaceutical compsns. for intravenous or intra-coronary admin. - are aq. emulsions contg. 1,4-di:hydro:pyridine calcium antagonist, natural oil and phosphatidyl-choline or phosphatidyl-ethanolamine
JPH08506081A (en) 1993-02-12 1996-07-02 ファーモス コーポレイション Dry composition for the preparation of submicron emulsions
SE9303657D0 (en) 1993-11-05 1993-11-05 Astra Ab Short-acting dihydropyridines
SE9303744D0 (en) 1993-11-12 1993-11-12 Astra Ab Pharmaceutical emulsion
GB9405593D0 (en) * 1994-03-22 1994-05-11 Zeneca Ltd Pharmaceutical compositions
IT1275532B (en) 1995-07-14 1997-08-07 Recordati Chem Pharm USE OF 1,4-DIHYDROPYRIDINIC DERIVATIVES FOR THE PREVENTION AND THERAPY OF THE ATHEROSCLEROTIC DEGENERATION OF THE ARTERIAL WALL
CN1227490A (en) 1996-08-07 1999-09-01 协和发酵工业株式会社 Fat emulsion containing xanthine derivative
PT1052975E (en) 1998-02-10 2007-10-29 Sicor Inc Propofol composition containing sulfite
IT1301807B1 (en) * 1998-06-25 2000-07-07 Tiberio Bruzzese INJECTABLE PHARMACEUTICAL FORMULATIONS OF DERIVATIVES OF PARTRICINE.
CN1146423C (en) 1998-07-14 2004-04-21 阿尔康实验室公司 Prostaglandin product
SE9804002D0 (en) 1998-11-23 1998-11-23 Astra Ab New manufacturing process
GB0012597D0 (en) 2000-05-25 2000-07-12 Astrazeneca Ab Formulation
US6858596B2 (en) 2000-08-05 2005-02-22 Smithkline Beecham Corporation Formulation containing anti-inflammatory androstane derivative
CA2494297C (en) 2002-07-29 2011-10-18 Transform Pharmaceuticals, Inc. Aqueous 2,6-diisopropylphenol pharmaceutical compositions
US20060094699A1 (en) 2003-04-11 2006-05-04 Kampen Gita Camilla T Combination therapy using an 11beta-hydroxysteroid dehydrogenase type 1 inhibitor and a glucocorticoid receptor agonist to minimize the side effects associated with glucocorticoid receptor agonist therapy
US20040265238A1 (en) * 2003-06-27 2004-12-30 Imtiaz Chaudry Inhalable formulations for treating pulmonary hypertension and methods of using same
US20050186230A1 (en) * 2004-01-23 2005-08-25 Sd Pharmaceuticals, Inc. Elemene compositions containing liquid oil
AU2005216298B2 (en) 2004-02-26 2010-09-02 Baylor Research Institute Compositions and methods for the systemic treatment of arthritis
US20050271710A1 (en) 2004-06-04 2005-12-08 Argo Brian P Antimicrobial tissue products with reduced skin irritation potential
US20050282895A1 (en) 2004-06-21 2005-12-22 Dosch Michael H Antimicrobial compositions and methods of use thereof
KR20080064171A (en) * 2005-10-20 2008-07-08 나스텍 파마수티컬 컴퍼니 인코포레이티드 Intranasal administration of rapid acting insulin
FR2900052B1 (en) 2006-04-19 2011-02-18 Galderma Sa COMPOSITION COMPRISING AT LEAST ONE AQUEOUS PHASE AND AT LEAST ONE FATTY PHASE COMPRISING IVERMECTIN
EP2054036B1 (en) 2006-07-24 2019-12-18 Singh-Broemer and Company, Inc. Solid nanoparticle formulation of water insoluble pharmaceutical substances with reduced ostwald ripening
US20080206170A1 (en) 2006-12-07 2008-08-28 Belinda Tsao Nivaggioli Creatine compositions for skin treatment
KR101607244B1 (en) 2007-06-11 2016-03-30 알. 로치 맥도날드 A drug delivery system for the prevention of cerebral vasospasm
EP2008651A1 (en) 2007-06-26 2008-12-31 Drug Delivery Solutions Limited A bioerodible patch
PL2320740T3 (en) * 2008-08-01 2014-09-30 The Medicines Co Pharmaceutical compositions of clevidipine and methods for producing low impurity concentrations of the same
US20100130619A1 (en) 2008-11-24 2010-05-27 Joseph Schwarz Pharmaceutical composition for parenteral administration of idebenone
CN101766668B (en) 2008-12-30 2011-11-23 上海中医药大学 Burdock extract and preparation method and application thereof
CN101766568A (en) 2008-12-31 2010-07-07 北京利乐生制药科技有限公司 Emulsion containing clevidipine and preparation process and application thereof
DE102009003980A1 (en) 2009-01-07 2010-07-08 B. Braun Melsungen Ag Formulation, useful for preventing propofol infusion syndrome, comprises propofol and a fatty emulsion with a triglyceride
CN101791311A (en) 2009-12-31 2010-08-04 广州中大创新药物研究与开发中心有限公司 Pharmaceutical composition with short pressure-reducing function
CN101780036B (en) 2010-03-30 2011-11-16 武汉武药科技有限公司 Butyrate clevidipine lipid microsphere injection and preparation method thereof
PT2627173E (en) 2010-10-12 2015-07-24 Medicines Co Clevidipine emulsion formulations containing antimicrobial agents

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20100105743A1 (en) * 2008-08-01 2010-04-29 Gopal Krishna Pharmaceutical compositions and methods for stabilizing the same
WO2010022259A1 (en) * 2008-08-22 2010-02-25 Milestone Pharmaceuticals Inc. Short acting benzothiazepine calcium channel blockers and uses thereof

Also Published As

Publication number Publication date
BR112013008601A8 (en) 2017-12-12
US10010537B2 (en) 2018-07-03
EA201390541A1 (en) 2013-11-29
WO2012051116A8 (en) 2013-05-02
EA022849B1 (en) 2016-03-31
PL2627173T3 (en) 2015-08-31
JP6040437B2 (en) 2016-12-07
KR20160032266A (en) 2016-03-23
NZ610465A (en) 2015-05-29
AU2011313852A1 (en) 2013-05-09
KR20130101080A (en) 2013-09-12
DK2627173T4 (en) 2018-10-22
HK1187495A1 (en) 2014-04-11
AU2011313852A8 (en) 2013-07-25
DK2627173T3 (en) 2015-07-06
KR101786857B1 (en) 2017-10-18
EP2627173A4 (en) 2014-05-07
CN103237446A (en) 2013-08-07
CA2814495C (en) 2018-07-31
AU2011313852B2 (en) 2015-07-02
EP2627173B2 (en) 2018-07-04
CA2814495A1 (en) 2012-04-19
BR112013008601A2 (en) 2017-07-25
JP2014196322A (en) 2014-10-16
ES2539861T5 (en) 2018-11-16
JP2016183183A (en) 2016-10-20
BR112013008601B1 (en) 2020-03-31
JP6437743B2 (en) 2018-12-12
PL2627173T5 (en) 2019-11-29
MX2013004151A (en) 2013-05-20
EP2627173B1 (en) 2015-03-25
EP2627173A1 (en) 2013-08-21
HUE026295T2 (en) 2016-06-28
JP6326094B2 (en) 2018-05-16
MX356537B (en) 2018-06-01
JP2014504259A (en) 2014-02-20
PT2627173E (en) 2015-07-24
ES2539861T3 (en) 2015-07-06
US20120088804A1 (en) 2012-04-12
WO2012051116A1 (en) 2012-04-19

Similar Documents

Publication Publication Date Title
CN103237446B (en) Clevidipine emulsion formulations containing antimicrobial agents
US20210369694A1 (en) Clevidipine emulsion formulations containing antimicrobial agents
US6528540B2 (en) Esmolol formulation
BRPI0616127A2 (en) argatroban formulation
RU2286774C2 (en) Esmolol-based preparation
US20210275500A1 (en) Liquid bendamustine pharmaceutical compositions
US20040171691A1 (en) Propofol with cysteine
US8754125B2 (en) Antimicrobial preservation of propofol emulsions

Legal Events

Date Code Title Description
C06 Publication
PB01 Publication
C10 Entry into substantive examination
SE01 Entry into force of request for substantive examination
REG Reference to a national code

Ref country code: HK

Ref legal event code: DE

Ref document number: 1187495

Country of ref document: HK

C14 Grant of patent or utility model
GR01 Patent grant
REG Reference to a national code

Ref country code: HK

Ref legal event code: GR

Ref document number: 1187495

Country of ref document: HK

C41 Transfer of patent application or patent right or utility model
TR01 Transfer of patent right

Effective date of registration: 20161019

Address after: Italy Palma

Patentee after: Chiesi Farmaceutici S. P. A.

Address before: new jersey

Patentee before: The Medicines Company

IW01 Full invalidation of patent right
IW01 Full invalidation of patent right

Decision date of declaring invalidation: 20160218

Decision number of declaring invalidation: 28247

Granted publication date: 20141105